Bladder pain and voiding dysfunction are the cardinal signs of IC/BPS. Patients with IC/BPS report enhanced pain on bladder filling (distension), and we recently found that these patients also demonstrate segmental referred hyperalgesia, reflecting the presence of central sensitization in IC/BPS. Referred hyperalgesia and pain on bladder distension seen in patients is also observed in animal models of IC/BPS, providing a laboratory model system for us to pursue the development of novel therapies for IC/BPS. Studies in animal models are needed to gain a clear understanding of the mechanisms of pain and voiding dysfunction in the context of bladder injury and IC/BPS, and this knowledge is necessary to develop novel mechanism-based therapies. Much regarding these mechanisms remains to be determined, and key among these unknowns is knowledge of what sensory neurons carry signals from the bladder to the central nervous system and what are the key receptors mediating bladder pain transmission. In this project, we will address these critical knowledge gaps. In Aim 1 we use optogenetic approaches to identify subpopulations of afferent neurons innervating the bladder that are responsible for carrying signals that regulate bladder pain and voiding dysfunction. This may form the basis for nonpharmacologic approaches to the management of IC/BPS. In Aims 2 and 3, we propose a translational research study aimed at a novel pharmacologic approach to managing pain and voiding dysfunction: inhibition of metabotropic glutamate receptor 5 (mGlu5). This includes preclinical studies identifying the site of action of the mGlu5 antagonist fenobam in Aim 2, and in Aim 3, we propose a proof of concept clinical study to test the efficacy of fenobam in treating bladder pain and voiding dysfunction in patients with IC/BPS. Together, the studies proposed here will provide key insights into the cells and signaling molecules that mediate bladder pain and voiding dysfunction in mice and in IC/BPS patients. This will be the first directly translational study of its kind, and may provide evidence supporting an entirely new therapeutic approach to the management of IC/BPS, as well as paving the way for new non-pharmacologic approaches using optogenetics as a therapeutic approach in the future.